The role of the multifaceted long non-coding RNAs: A nuclear-cytosolic interplay to regulate hyaluronan metabolism

In the extracellular matrix (ECM), the glycosaminoglycan (GAG) hyaluronan (HA) has different physiological roles favouring hydration, elasticity and cell survival. Three different isoforms of HA synthases (HAS1, 2, and 3) are responsible for the production of HA. In several pathologies the upregulation of HAS enzymes leads to an abnormal HA accumulation causing cell dedifferentiation, proliferation and migration thus favouring cancer progression, fibrosis and vascular wall thickening. An intriguing new player in HAS2 gene expression regulation and HA production is the long non-coding RNA (lncRNA) hyaluronan synthase 2 antisense 1 (HAS2-AS1). A significant part of mammalian genomes corresponds to genes that transcribe lncRNAs; they can regulate gene expression through several mechanisms, being involved not only in maintaining the normal homeostasis of cells and tissues, but also in the onset and progression of different diseases, as demonstrated by the increasing number of studies published through the last decades. HAS2-AS1 is no exception: it can be localized both in the nucleus and in the cytosol, regulating cancer cells as well as vascular smooth muscle cells behaviour. •Hyaluronan is a component of the extracellular matrix and is synthetised by three isoenzymes named HAS1, 2, and 3.•In several pathologies an upregulation of HAS2 leads to an abnormal accumulation of HA.•The long non-coding RNA is a new specific epigenetic regulator of HAS2.•In the nucleus HAS2-AS1 modulates chromatin structure around HAS2 promoter increasing transcription.•In the cytosol, HAS2-AS1 can interact with several miRNAs altering the expression of several genes as well as can stabilise HAS2 mRNA forming RNA: RNA duplex.